Nuclear matrix binding is critical for progesterone receptor movement into nuclear foci.
The ovarian hormone progesterone is essential for normal breast development, and progesterone analogues are implicated in increasing breast cancer risk. The progesterone receptor (PR) is a transcription factor that, when ligand activated, moves rapidly into nuclear foci associated with transcriptional activity. However, the role of intranuclear trafficking signals in the focal location of PR is unknown. We have identified a mutation in PR that ablates its binding to the nuclear matrix and prevents PR movement into nuclear foci. Nuclear matrix binding mutants lack transcriptional activity and inhibit dimerization, demonstrating the critical role of matrix binding for PR dynamics and activity. DNA binding of PR is required for fidelity of location in foci, as DNA binding domain (DBD) mutants form aberrant foci with reduced mobility and altered tethering to the nucleus. Mutations in either the nuclear matrix targeting sequence or DBD domains were dominant in preventing wild-type receptor from moving to appropriate nuclear locations, demonstrating that both partner proteins in a PR dimer must have intact intranuclear trafficking signals for correct receptor positioning within the nucleus. This study has demonstrated that positioning of PR in foci within the nucleus is critically regulated by intranuclear trafficking signals, which play a key role in transcriptional activity and are relevant to its action in normal and malignant breast cells.
Graham
J Dinny
JD
Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia.
Hanson
Adrienne R
AR
Croft
Amanda J
AJ
Fox
Archa H
AH
Clarke
Christine L
CL
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D015530:Nuclear Matrix / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D011980:Receptors, Progesterone; D004247:DNA